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VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells.
Mondru, Anil Kumar; Aljasir, Mohammad A; Alrumayh, Ahmed; Nithianandarajah, Gopika N; Ahmed, Katie; Muller, Jurgen; Goldring, Christopher E P; Wilm, Bettina; Cross, Michael J.
Afiliación
  • Mondru AK; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Aljasir MA; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Alrumayh A; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Nithianandarajah GN; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Ahmed K; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Muller J; Cardiovascular Research Group, School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK.
  • Goldring CEP; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • Wilm B; Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK.
  • Cross MJ; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
Cells ; 12(6)2023 03 22.
Article en En | MEDLINE | ID: mdl-36980305
Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factor A de Crecimiento Endotelial Vascular / Proteína Quinasa 7 Activada por Mitógenos / Proteínas Proto-Oncogénicas c-akt Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factor A de Crecimiento Endotelial Vascular / Proteína Quinasa 7 Activada por Mitógenos / Proteínas Proto-Oncogénicas c-akt Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article